We have recently demonstrated for the first time that the hydrolytic stability of labile phosphoramidates can be strategically regulated by triorganosilylation of the double bond P(O) -NH moiety. The synthesized lipophilic trimethylsilylated phosphoramidates have been designed such that non-enzymatic desilylation takes place under physiological conditions (37 degrees, oH 7.7) to give an "unmasked" phosphoramidate, which then undergoes relatively rapid elimination to generate a metaphosphorimidate species capable of intercepting biological nucleophiles. Based on these results, strategically triorganosilylated carbamates, phosphoramidates, and phosphoramidic mustard, as well as selected 14 C-labelled members of these intended anti-cancer pro-drug classes, will be synthesized. The hydrolytic stability of these compounds will be investigated in vitro to obtain structures having optimized lability features with regard to removal of the protective triorganosilyl group. Lipophilic polyaromatic sulfines will be synthesized and examined with regard to DNA complexation. Brain uptake measurements using the Olderdorf procedure will be performed on likely candidate compounds in order to provide information regarding the ability of these potential CNS pro-drugs to cross the blood brain barrier. To facilitate decisions regarding the efficiency of our pro-drug strategies, measurements of activity against L1210 via Protocol 11 will be obtained.